The Treatment Potential of Innate lymphocytes for HIV infection

Written by Professor Derek G. Doherty, Discipline of Immunology, School of Medicine, Trinity College Dublin

The Treatment Potential of Innate lymphocytes for HIV infection

The current COVID-19 pandemic has shifted attention away from the human immunodeficiency virus (HIV) pandemic which has been ongoing for 40 years and has claimed over 36 million lives. And it is not over – currently there are more than 37 million people living with HIV. Until the mid-1990s, a positive HIV test meant almost certain progression to death within 10-15 years, but now with antiretroviral therapy (ART), HIV-positive people can live relatively normal healthy lives. Over 60% of people with HIV live in sub-Saharan Africa, and equitable access to ART in these regions took many years. But now over 27 million people worldwide are on ART for HIV – about 73% of the people who need it. With 1.5 million new infections every year and the majority being treated, the number of people living with HIV is increasing year on year.

The immunodeficiency caused by HIV is the result of the virus infecting and killing CD4 T cells.

CD4 T cells are the commanders of adaptive immune responses. They learn the nature of the threat to the body, be it a virus, a bacterium, a parasitic worm or a tumour, and they release cytokines, chemical messengers that recruit and activate the appropriate weapons of the immune response. But CD4 T cell numbers decline during HIV infection and when they drop below 200 per microlitre of blood, the body is defenseless against a myriad of pathogens and tumours, the condition termed the acquired immunodeficiency syndrome (AIDS). People with AIDS are susceptible to infections by many pathogens, with tuberculosis being the most common cause of death.

Despite the major advances in vaccine development, a vaccine against HIV has yet to be produced.

To date, the best result has been the RV144 clinical trial, which was tested on more than 16,000 subjects and resulted in 31% protection against persistent HIV infection after 3 years. There are several reasons for the failure to develop an efficacious vaccine against HIV. In addition to the depletion of CD4 T cells, which are required for responses to vaccines, HIV has evolved many tricks to evade or subvert the immune system. Being an RNA virus, HIV is particularly susceptible to mutations occurring during replication, leading to the generation of new variants that escape recognition by T cells and antibodies. HIV can exist in latent form with its genome integrated into the host cell genome and no virus particles present, making it invisible to the immune system, but capable of later re-emerging as replicating virus. HIV also produces a protein, called Nef, which can specifically inhibit components of the immune system.

As mentioned above, CD4 T cells are the commanders of the immune system. CD4 T cells give the orders to CD8 T cells and other cells to kill virus-infected cells. CD4 and CD8 T cells have cell-surface antigen receptors that specifically recognize peptide fragments of proteins derived from viruses and other pathogens, allowing exquisite specificity in adaptive immune responses. Less studied are ‘innate T cells’ – unconventional T cells that do not recognise peptides – instead they recognize lipids, phosphates or other metabolites produced by pathogens or by host cells in response to infection by pathogens. Many of the antigens recognized by innate T cells are common to many different microorganisms, meaning that innate T cells do not display the high degree of antigen-specificity seen for conventional T cells.

However, innate T cells exhibit many properties that make them essential contributors to antiviral immunity.

Firstly, they recognize antigens that are not encoded by DNA and therefore are not subject to mutational changes. Secondly, while conventional T cells take several days to differentiate into effector cells after antigen recognition, innate T cells exist as effector cells and can elicit their effector functions within minutes. Once activated, they can kill virus infected cells and release early bursts of cytokines that recruit and activate other cells of the immune system, thereby shaping and polarizing adaptive immune responses. Innate T cells can activate and regulate dendritic cells, macrophages, neutrophils, natural killer cells, myeloid derived suppressor cells and conventional T cells via contact dependent and cytokine-mediated interactions. Importantly, innate T cells can promote antigen presentation by dendritic cells and antibody production by B cells – essential for immunity against viruses. Furthermore, they can selectively promote or suppress the responses of other immune cells. Research by us and others is attempting to figure out how to selectively turn on or off individual functional activities of innate T cells in order to therapeutically activate the appropriate immune responses to combat particular pathogens.

Three subsets of innate T cells are depleted from the circulation of people with HIV and especially people who progress to AIDS.

These are natural killer T (NKT) cells, mucosa-associated invariant T (MAIT) cells and a subset of gamma/delta (γδ) T cells, termed Vδ2 T cells. These depletions could be due to activation induced cell death, killing by the virus, or migration to particular tissues such as the gut, but several lines of evidence suggest that they are contributing to immunity against HIV. In particular, Vδ2 T cells which recognize phosphate antigens, can kill HIV infected cells, including latently infected cells, and inhibit HIV replication within cells. Therefore, it is likely that restoration and activation of Vδ2 T cell numbers will promote immunity against HIV and may be used as an adjunct to ART. Immunotherapies utilising Vδ2 T cells are showing promise in clinical trials for cancer. Strategies employed include in vivo activation of Vδ2 T cells using phosphate antigens – this can be achieved using aminobis phosphonate drugs, such as zoledronate and pamidronate, which are licenced for the treatment of bone resorption diseases but also activate Vδ2 T cells by inducing the production of endogenous phosphates. Alternatively, Vδ2 T cells can be isolated from patients’ blood and expanded ex vivo using aminobisphosphonates or phosphate antigens, before being adoptively transferred back to the patient. Similar clinical trials for cancer are ongoing using glycolipids to activate NKT cells either in vivo or ex vivo in adoptive transfer regimens. Future work is required to determine if innate T cells can similarly be used to treat infectious diseases.

Innate T cells show promise as targets for therapy for HIV infection.

Since they are activated by conserved non-peptide ligands, they can be easily expanded to high numbers in tissue culture. Their functions can be ‘tweaked’ to optimise their antiviral activities by stimulating with various synthetic ligands in the presence of particular cytokines. Clinical trials involving NKT cells and γδ T cells are ongoing in cancer patients with promising results. The next step is to take these treatments into patients with infectious disease, and HIV remains the holy grail for such therapies.

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